Linking metabolism to ageing: a new role for histone lysine acetylation

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Healthy ageing is influenced by diet and light/dark cycles that control the interconnected metabolic and circadian cycles within cells. We study baker's yeast, which has a metabolic cycle and ages similarly to humans, providing a tractable system to discover the processes that coordinate cycles and ageing. Research aimed at discovering new ways of improving healthy ageing is rising to prominence, with work addressing the basic biology of ageing likely to underpin future medical advances. Much of our knowledge of the molecular processes involved in ageing has come from work using simple eukaryotes as model organisms. Furthermore, many of the genes and processes involved in ageing are conserved across evolution. We plan to investigate a new pathway linked to ageing at the fundamental level of gene expression, and the control of ageing by the metabolic state of the cell. In this project we will use a single-cell eukaryote, the yeast Saccharomyces cerevisiae. Yeast has many advantages for this work. We can synchronize yeast in their metabolic cycle meaning that we can study whole populations of cells with identical metabolic states. Yeast is one of the only systems in which it is possible to directly study the effect of metabolism on gene expression. Genes are packaged into chromatin, a complex of DNA and protein that influences gene expression. The chromatin is chemically modified in a reaction driven by the metabolic state of the cell, allowing gene expression and metabolism to be coordinated. It is generally believed that these chemical modifications influence the first step of gene expression, known as transcription, the copying of the genetic information in the DNA to the intermediate molecule RNA, which the then used as a template for the synthesis of proteins. We have discovered a new link between the chromatin and the last step of gene expression, the translation of the genetic information carried in RNA molecules into protein. This discovery was made possible by our ability to study particular regions of the chromatin that undergo chemical modifications in yeast, not possible in other organisms. This also enabled us to link this particular site of chemical modification on the chromatin to ageing in yeast. The purpose of this project is to understand how the chromatin influences translation of proteins and ageing. The characteristics of a cell, including how it ages, are controlled by proteins, in particular the amount of protein synthesized during translation. The production of proteins is central to cellular cycles and ageing, and is controlled by diet/nutrients, but the detailed processes are not understood. Defining these processes will contribute in the future to rational drug design aimed at alleviating symptoms of age-related conditions. Neurodegenerative conditions, for example, arise due to defects in the structures adopted by proteins, causing loss of normal function and cell death. The accumulation of defective proteins can be alleviated by altering how fast they are produced, and in yeast this leads to improved long-term viability of cells. In summary, we have discovered a novel nutrient-dependent target in chromatin that controls how fast proteins are produced and propose to dissect exactly how this is achieved. This work has important implications for understanding how diet and rhythmic cycles influence protein production and the molecular mechanisms behind age-related conditions.